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Process for producing efonidipine hydrochloride preparations

a technology of efonidipine and hydrochloride, which is applied in the direction of phosphorous compound active ingredients, biocide, animal husbandry, etc., can solve the problems of poor absorbability and high production cost, and achieve the effect of improving the surface properties and wettability of solid dispersion

Inactive Publication Date: 2001-01-09
NISSAN CHEM IND LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

A solid dispersion having not only an improved wettability of the surface of the solid dispersion but also a superior absorbability can be formed by dipping treatment into a water-containing solution, impregnation treatment with a water-containing solution or contacting treatment with a water vapor-containing gas in the step B. This method can increase the molecular motion between the amorphous substance of efonidipine hydrochloride and HPMC-AS, making it possible to increase a micro-dispersion and to delocalize the localized amorphous substance of efonidipine hydrochloride.
The solid dispersion of efonidipine hydrochloride obtained by the conversion to the amorphous state in the present invention is sprayed with water, a surfactant aqueous solution or an organic solvent such as ethanol or the like, or treated therewith in solution either as such or after being milled, and is then redried, making it possible to improve the surface properties and the wettability of the solid dispersion.

Problems solved by technology

Efonidipine hydrochloride is a slightly-soluble medication, and has, therefore, a poor absorbability.
However, it was problematic in that since a large amount of an organic solvent is used, the production cost is high, and the solvent sometimes remains in the medication.

Method used

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  • Process for producing efonidipine hydrochloride preparations
  • Process for producing efonidipine hydrochloride preparations

Examples

Experimental program
Comparison scheme
Effect test

example 2

Sixty grams of efonidipine hydrochloride, 180 g of HPMC-AS and 30 g of water were mixed, and the mixture was subjected to wet granulation using a universal mixer. The resulting wet granules were heated at 95.degree. C. for 2 hours using a hot air dryer, and further brought into contact with a steam for 60 minutes in a constant temperature and humidity chamber of 85.degree. C. and 90-% RH to obtain a solid dispersion. This solid dispersion was identified to be the same amorphous substance as that obtained in Example 1 through the powder X-ray diffractometry.

example 3

A mixture of 3 g of efonidipine hydrochloride, 6 g of HPMC-AS and 1.5 g of urea was subjected to mechanochemical treatment at room temperature (from 15 to 25.degree. C. ) and 100 G for 3 minutes using a high-speed planetary mill, and then milled. Water (1.5 g) was added thereto, and the resulting mixture was heated at 90.degree. C. for 30 minutes to obtain a solid dispersion. The powder X-ray diffractometry of this solid dispersion was conducted. Consequently, no crystal peak was identified.

example 4

Sixty grams of efonidipine hydrochloride, 180 g of HPMC-AS, 30 g of urea and 30 g of water were mixed, and the mixture was subjected to wet granulation using a universal mixer. The wet granules were subjected to the microwave heating for 4 minutes using a microwave heater (2450 MHz, 500 W) to obtain a solid dispersion. At that time, the final temperature was 130.degree. C.

The powder X-ray diffractometry of this solid dispersion was conducted. Consequently, no crystal peak was identified.

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Abstract

An amorphous solid dispersion of efonidipine hydrochloride having a high intestinal absorbability can be formed by subjecting a mixture containing efonidipine hydrochloride of the formula (I), hydroxypropylmethylcellulose acetate succinate and optionally a thermostabilizer to a step A of heat treatment at from 85 to 140° C. or mechanochemical treatment at from 0 to 140° C., and then to a step B of dipping treatment into a water-containing solution, impregnation treatment with a water-containing solution or contacting treatment with a water vapor-containing gas; or treating the above-mentioned mixture with a hot steam at from 100 to 140° C. and a high pressure. Further, in the above-mentioned step A, the mixture is subjected to high frequency heating, making it possible to give a solid dispersion of efonidipine hydrochloride having a high intestinal absorbability without using the step B. This process is quite advantageous in the production in that the use of an organic solvent is not required. Formula (I):

Description

The present invention relates to a process for producing a novel solid dispersion of a 1,4-dihydro-2,6-dimethyl-5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-nitrophenyl)-3-pyridinecarboxylic acid 2-[benzyl(phenyl)amino]ethyl ester hydrochloride-ethanol solvate (1:1) (hereinafter referred to as "efonidipine hydrochloride") which has an antihypertensive activity, and to oral preparations containing this solid dispersion.Efonidipine hydrochloride which is an active ingredient of a pharmaceutical preparation produced by the present invention is a 1,4-dihydropyridine-5-phosphonic acid derivative of the formula: ##STR2##and it is a compound which is useful as a medication for circulatory organs having a vasodilative activity and an antihypertensive activity owing to a calcium antagonism.Efonidipine hydrochloride is a slightly-soluble medication, and has, therefore, a poor absorbability. In order to increase the absorbability, there are a method in which particles of an origina...

Claims

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Application Information

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IPC IPC(8): A61K31/66A61K31/675A61K9/14A61K9/16
CPCA61K9/145A61K9/146A61K9/1617A61K9/1652A61K31/66A61K31/675
Inventor MIYAMOTO, MISAOODA, TOSHIHISABUNRIN, TOYOHIKOOKABE, TOSHIONISHIYAMA, TETSUYUKI
Owner NISSAN CHEM IND LTD